State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Aging (Albany NY). 2024 Mar 7;16(5):4904-4919. doi: 10.18632/aging.205642.
Stem cell therapy requires massive-scale homogeneous stem cells under strict qualification control. However, Prolonged expansion impairs the biological functions and results in senescence of mesenchymal stem cells (MSCs). We investigated the function of CTDSPL in the premature senescence process of MSCs and clarified that miR-18a-5p played a prominent role in preventing senescence of long-term cultured MSCs and promoting the self-renewal ability of MSCs. Over-expression of CTDSPL resulted in an enlarged morphology, up-regulation of p16 and accumulation of SA-β-gal of MSCs. The reduced phosphorylated RB suggested cell cycle arrest of MSCs. All these results implied that CTDSPL induced premature senescence of MSCs. We further demonstrated that miR-18a-5p was a putative regulator of CTDSPL by luciferase reporter assay. Inhibition of miR-18a-5p promoted the expression of CTDSPL and induced premature senescence of MSCs. Continuous overexpression of miR-18a-5p improved self-renewal of MSCs by reducing ROS level, increased expression of Oct4 and Nanog, and promoted growth rate and differentiation capability. We reported for the first time that the dynamic interaction of miR-18a-5p and CTDSPL is crucial for stem cell senescence.
干细胞治疗需要在严格的资格控制下大规模同质的干细胞。然而，长期扩增会损害间充质干细胞（MSCs）的生物学功能，并导致其衰老。我们研究了 CTDSPL 在 MSCs 衰老过程中的作用，并阐明了 miR-18a-5p 在防止长期培养的 MSCs 衰老和促进 MSCs 自我更新能力方面发挥了重要作用。CTDSPL 的过表达导致 MSCs 的形态增大，p16 上调和 SA-β-gal 积累。RB 的磷酸化减少表明 MSCs 的细胞周期停滞。所有这些结果表明 CTDSPL 诱导 MSCs 过早衰老。我们进一步通过荧光素酶报告基因检测证实了 miR-18a-5p 是 CTDSPL 的一个假定调节剂。miR-18a-5p 的抑制促进了 CTDSPL 的表达，并诱导了 MSCs 的过早衰老。持续过表达 miR-18a-5p 通过降低 ROS 水平、增加 Oct4 和 Nanog 的表达，以及促进生长速度和分化能力，改善了 MSCs 的自我更新能力。我们首次报道了 miR-18a-5p 和 CTDSPL 的动态相互作用对干细胞衰老至关重要。
